Due to the escalating incidence rate of melanoma in the USA and its high frequency to metastasize to the brain, melanoma brain metastasis (MBM) poses an increasingly significant clinical problem. In the absence of predictive biomarkers for MBM, early recognition and effective management of MBM remain inadequate to the detriment of the nation's healthcare economy and patients' quality of life. We will identify genomic and epigenomic aberrations that are signatures of MBM. We will then develop and verify these molecular aberrations as predictive molecular MBM biomarker signature(s) of stage III and IV melanomas for high-risk of MBM occurrence. Our main hypothesis is that specific genomic and epigenomic biomarkers can be identified as signatures of MBM and utilized for stage III and early stage IV melanoma metastasis for MBM occurrence. The specific Aims are based on our strong preliminary studies on genomic and epigenomic aberrations identified in MBM. The Specific Aims are as follows: Aim I. Identify and develop a signature panel of MBM genomic biomarkers that can be used as predictive biomarkers in stage III and IV melanoma for MBM occurrence. Single-nucleotide polymorphism (SNP) will be used to identify copy number variations (CNV) for losses and gains as predictive biomarkers using customized quantitative PCR assays. Prioritized MBM genomic biomarkers will then be assessed as predictors of MBM occurrence. Aim II. Identify and develop a signature panel of epigenomic MBM biomarkers that can be used as predictive biomarkers in stage III and early stage IV for MBM occurrence. Methylation array and quantitative methylation-specific PCR assays have been used to screen and identify biomarker signatures of MBM. These predictive MBM epigenomic biomarkers will then be developed and analyzed by optimized quantitative methylation-specific PCR assays. Prioritized MBM epigenomic biomarkers will then be assessed as predictors of MBM occurrence. Aim III. Verify a MBM predictive signature(s) of genomic and/or epigenomic MBM biomarkers for stage III and IV metastasis. The optimal MBM biomarker signature panel identified in Aims I and II will be tested in patients with stage III and IV metastases, respectivey, for their ability to predict MBM occurrence using phase III multicenter clinical trial patients who have undergone surgical resection to be rendered disease-free. The studies will verify high-risk stage III and IV patients' melanoma subtypes developing into MBM, identification of new targets for therapy, and identification of MBM molecular signatures.